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Hi
I understand from the EMEA guidelines that widening of the Cmax
confidence intervals (to 75-133%) is possible for bioequivalence of
highly variable drugs. Does anybody know whether this can be argued
for AUC as well? Does anybody have any experience in discussing this
with the EMEA.
Thanks
Meena Sarasia
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Hi Meena,
I think the same EMEA guideline also states that "In rare cases a
wider accpetance range may be acceptable if it is based on sound
clinical judgement".
Thanks
Ganesh M Mugundu
Graduate Student
College of Pharmacy
University of Cincinnati
Blog: http://pk-pd.blogspot.com/
WebPage: www.geocities.com/ganaish
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The following message was posted to: PharmPK
Hi Meena,
The answer to your first question is in the first question of the
EMEA's Q&A guidance on BE:
"The possibility offered here by the guideline to widen the acceptance
range of 0.80 - 1.25 for the ratio of Cmax (not for AUC) should be
considered exceptional and limited to a small widening (0.75 1.33)."
Source: Questions & Answers on the Bioavailability and Bioequivalence
Guideline; EMEA/CHMP/EWP/40326/2006
http://www.emea.europa.eu/pdfs/human/ewp/4032606en.pdf
The guidance also has some further details of the requirements for
using widened limits. I've never discussed it with the EMEA as the
guidance is clear.
Hope this helps,
-Dave
--
David Dubins, Ph.D., B.A.Sc.
Global Bioequivalence Consulting
Assistant Professor, Leslie Dan Faculty of Pharmacy
University of Toronto
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The following message was posted to: PharmPK
Hi,
Widening of CI is only for Cmax, not for AUC. According to Questions &
Answers on the Bioavailability and Bioequivalence Guideline by EMEA
The possibility offered here by the guideline to widen the acceptance
range of 0.80 - 1.25 for the ratio of Cmax (not for AUC) should be
considered exceptional and limited to a small widening (0.75 1.33).
Please also see EMEA/CHMP/EWP/40326/2006
http://www.emea.europa.eu/pdfs/human/ewp/4032606en.pdf.
Thanks
Ravi
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The following message was posted to: PharmPK
I understand from EMEA guidelines that widening is only to Cmax.
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Please check page 10 of EMEA guideline under AUC ratio where it states
' wider acceptance range may be acceptable if it is based on sound
clinical justification".
http://www.emea.europa.eu/pdfs/human/ewp/140198en.pdf
Ganesh
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According. However it is very hard to show this justification clinic.
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The following message was posted to: PharmPK
Dear Ganesh!
> Please check page 10 of EMEA guideline under AUC ratio where it
states
> ' wider acceptance range may be acceptable if it is based on sound
> clinical justification".
>
> http://www.emea.europa.eu/pdfs/human/ewp/140198en.pdf
Your reference to the European Note for Guidance is valid, but outdated!
As David Dubins already stated in a previous post, everybody interested
in applying to a European member state should *also* refer to the
Questions & Answers Document, which was published by EMEA's 'Therapeutic
Subgroup on Pharmacokinetics' (EWP-PK) on 27 July 2006.
Although no draft version was published, according to the Monthly Report
from CHMP's Plenary Meeting (24 a 27 July 2006:
http://www.emea.europa.eu/pdfs/human/press/pr/29618506en.pdf), and the
Clinical Efficacy and Safety Guidelines
(http://www.emea.europa.eu/htms/human/humanguidelines/efficacy.htm) the
document is adopted by the EMEA and operational with July 2006.
Interesting Sections are
#2 Assessment of Cmax in bioequivalence studies.
In which cases is it allowed to use a wider acceptance range for the
ratio of Cmax?
#8 What is a "highly variable drug or drug product"?
ad #2:
[...] The possibility offered here by the guideline to widen the
acceptance range of 0.80 a 1.25 for the ratio of Cmax (*not for AUC*)
should be considered exceptional and limited to a small widening (0.75 a
1.33).
Furthermore, this possibility is restricted to those products for which
at least one of the following criteria applies:
1. Data regarding PK/PD relationships for safety and efficacy are
adequate to demonstrate that the proposed wider acceptance range for
Cmax does not affect pharmacodynamics in a clinically significant way.
2. If PK/PD data are either inconclusive or not available, clinical
safety and efficacy data may still be used for the same purpose, but
these data should be specific for the compound to be studied and
persuasive.
3. The *reference product has a highly variable within-subject
bioavailability*. Please refer to the Question on highly variable drug
or drug products for guidance on how to address this issue at the
planning stage of the bioequivalence trial.
A post hoc justification of an acceptance range wider than defined in
the protocol cannot be accepted. Information that would be required to
justify results lying outside the conventional acceptance range at the
post hoc stage should be utilised at the planning stage, either for a
scientific justification of a wider acceptance range for Cmax, or for
selecting an experimental approach that allows the assessment of
different sources of variability.
Remark: Some European countries are happy with (3) - but others (like
Sweden) want to see additionally (1) and/or (2). This is against the Q&A
document, but current practice.
ad #8:
[...] A drug product is called highly variable if its intra-individual
(i.e. within-subject) variability is greater than 30%. *A high CV* as
estimated from the ANOVA model *is thus an indicator* for high
within-subject variability. However, a replicate design is needed to
assess within-subject variability.
Remark: According to #2(3), intra-subject CVs of >30% from previous 2x2
cross-over studies are no more accepted to justify widening of the
acceptance range (for Cmax only). A replicate design pilot study
(according to LA!zlA TAthfalusi preferrably TRT-RTR) is necessary to
demonstrate high intra-subject variability of the reference product.
The main study (with widened AR) may be performed e.g. as a simple 2x2
cross-over in N subjects, or replicate designs (2-treatment 2-sequence
4-period in N/2 subjects, or 2-treatment 2-sequence 3-period in N*3/4
subjects).
Best regards,
Helmut
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
e-mail helmut.schuetz.aaa.bebac.at
web http://bebac.at/
contact http://bebac.at/Contact.htm
forum http://forum.bebac.at/
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